Design, Synthesis And Evaluation Of Benzimidazole Derivatives As A Novel Class Of HIV Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

AIDS has become one of the most serious epidemic diseases that threat to human health and life. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) with structural diversity have, in addition to other kinds of drugs, gained a significant place in the treatment of HIV-1 infections because of their low toxicity, high potency , and statistical synergy with other anti-HIV drugs. However, an obvious disadvantage of NNRTls is rapid emergence of virus-drug resistance due to mutations of the amino acids surrounding the NNRTI-binding site. Therefore, it is critical to explore novel types of NNRTls effective against drug-resistance. This research was focused on seeking a novel class of potent NNRTls leads following the de novo strategy based on the structure of target binding site and the 3D-QSAR information of ligands.First of all, the 3D-QSAR models of CoMFA and CoMSIA were established based on diverse structures and bio-data of known NNRTls. Then, the anti-HIV activities of a lot of designed compounds were predicted by 3D-QSAR models, and several 1,2-aryl/benzyl/phenylamino benzimidazole derivatives were found to be potential NNRTI agents. Following the theoretical computation, 26 of 1,2-substituted benzimidazole derivatives were designed and synthesized. All the new compounds were evaluated anti-HIV activities in MT-2 cell lines and three promising anti-HIV hits, T-24, T-11, and T-1, were found. Compound T-24 exhibited very potent anti-HIV activity with an EC₅₀ value of 9.81 μM in MT-2 cell assay and was confirmed in MT-4 cell assay (EC₅₀ = 48.14 μM). Unfortunately, T-24 also showed high toxicity in both cell lines with TI values of 2.51 and 2.93, respectively. Comparing with T-24, T-11 exhibited similar potency of anti-HIV activity with an EC₅₀ value of 15.3 μM and much lower toxicity (CC5o=234.2μM). Furthermore, compound T-1 showed very potent anti-HIV activity in MT-4 and MT-2 cell lines as well as HIV-RT assay with EC₅₀ values of 3.22 μM, 69.9 μM and 45.7 μM, respectively. The initial SAR studies indicated: (1) the presence of a linker of methene at the N-1 may be beneficial to anti-HIV activity, while longer chain could enhance toxicity; (2) substituted phenyl at the C-2 could reduce toxicity; (3) 6-substituted benzimidazoles generally showed higher anti-HIV activity than 5-substuted ones; (4) the presence of a halogenated benzyl ring at the N-l would enhance anti-HIV potency and decrease cytotoxicity.In summary, we have found out three promising anti-HIV compounds, T-24, T-11, and T-1, and initial SAR results in this preliminary studies. Current results will helpfully guide us further studies for optimizing and designing more benzimidazole derivatives as novel NNRTls lead compounds.